Transforming growth factor beta (TGF-beta) is a potent inhibitor of cell proliferation. Yet many cancer cells are resistant to the growth inhibition by TGF-beta while maintaining other aspects of TGF-beta responses that benefit tumor progression. The mechanism for such cell-context dependency in TGF-beta function remains a challenging and important question. Recent studies have suggested that the magnitude and duration of TGF-beta signaling into the nucleus is a critical determinant of the nature of TGF-beta response in the recepient cells. My laboratory is interested in studying the mechanism and regulation of nucleocytoplasmic translocation 3f Smad proteins, a process that controls the strength and duration of TGF-beta signaling. Modulation of nucleocytoplamic trafficking of Smads is also an important aspect of how TGF-beta signal is interpreted differently by cancer cells. In this proposal, we study regulation of Smad movement that leads to down- regulation of TGF-beta signaling into the nucleus. Specifically, we will pursue the following: Aim#1. TGF-beta-regulated nuclear export of Smad7. Aim#2. Regulation of Smad trafficking by TGF-beta and mitogenic signals. Aim#3. Protein Ser/Thr phosphatase against phosphorylated Smad2 (Smad2-P). The outcome of this study will shed light on how the level and duration of TGF-beta nucleus is regulated. Identifying key molecules in controlling Smad trafficking will also sensitize or desensitize cells to TGF-beta. These regulators of subcellular localization potential targets for therapeutic interventions aimed at modulating TGF-beta signaling diseases such as cancer.